Stabilization of quinapril using magnesium oxide

ABSTRACT

The present invention is directed to ACE inhibitor-containing compositions stabilized by the presence of magnesium oxide. Preferably, the ACE inhibitor, quinapril, is protected from certain forms of degradation when prepared in a pharmaceutical composition consisting essentially of magnesium oxide as the stabilizing agent. The presence of magnesium oxide also lends itself to favorable processing conditions during the manufacture of ACE inhibitor-containing compositions, especially processing by wet granulation.

This application is a 371 of PCT/US99/10189 filed May 10,1999, whichclaims priority under 35 U.S.C. §119(e) to Provisional Application No.60/088,280 filed Jun. 5, 1998.

FIELD OF THE INVENTION

The present invention is directed to ACE inhibitor-containingcompositions stabilized by the presence of magnesium oxide. Preferably,the ACE inhibitor, quinapril, is protected from certain forms ofdegradation when prepared in a pharmaceutical composition consistingessentially of magnesium oxide as the stabilizing agent. The presence ofmagnesium oxide also lends itself to favorable processing conditionsduring the manufacture of ACE inhibitor-containing compositions,especially processing by wet granulation.

BACKGROUND OF THE INVENTION

Certain ACE (Angiotensin Converting Enzyme) inhibitors, which are usefulas antihypertensives, are susceptible to certain types of degradation.Specifically, quinapril and structurally-related drugs can degrade via(1) cyclization via internal nucleophilic attack to form substituteddiketopiperazines, (2) hydrolysis of the side-chain ester group, and (3)oxidation to form products having often unwanted coloration.

U.S. Pat. No. 4,743,450 discloses that stable compositions containingACE inhibitors of the type discussed above can be produced using certainadditives as stabilizers. Specifically, this patent discloses that theinorganic salts of metals of Group I and II of the Periodic Table act asstabilizers of ACE inhibitor-containing formulations susceptible tocertain types of degradation. Magnesium carbonate is taught to be apreferred stabilizer.

One ACE inhibitor, quinapril HCl, is sold commercially under thetradename, ACCUPRIL®, and employs magnesium carbonate hydroxide in itsformulations. Magnesium carbonate hydroxide contains approximately 40%to 42% magnesium oxide.

While magnesium carbonate hydroxide acts as an effective stabilizer ofquinapril, its use in pharmaceutical formulations represents certaindisadvantages. Magnesium carbonate hydroxide is a white, bulky powderwhich is difficult to formulate into tablets because of its poorcompressibility, moldability, and flowability. The difficultiesencountered by the use of magnesium carbonate hydroxide to formulate ACEinhibitor-containing compositions is accentuated when the compositionsare manufactured using a wet granulation process.

The preparation of granulations for tableting by wet granulation is theoldest and still the most widely used. Before dry compaction became aviable process, wet granulation was—for all practical purposes—the onlymethod available. However, it is laborious, involving considerablematerial handling, as well as several processing steps, and therefore itis costly. In general, the technique involves no more than theincorporation of a granulating fluid into the mixed, powdery tabletingredients (including at least some tableting aids) in such an amountand manner as to convert them into a uniform, moist, coherent, non-pastymass, which then is formed into moist granules of fairly uniform size,usually by forcing the mass through a screen. Thereafter, the moistgranules are dried and rescreened to break down agglomerates, andfinally blended with other tableting aids so as thus to arrive at thegranulation ready for tableting.

It will be noted that in wet granulation, the tablet ingredients besidesthe active matter also conventionally include other, pharmacologicallyinert materials, certainly tableting aids and perhaps also bulkingagents. Some of such tableting aids may be included in the mixed,powdery ingredients before the granulating fluid is incorporatedtherein, while further tableting aids may be applied to the surfaces ofthe granules, and in between them, after the granules have been formedand before the granulate is passed to the tableting machine.

The labor and cost so characteristic of wet granulation processes arecommon when compounds like magnesium carbonate hydroxide are mixed withACE inhibitors like quinapril HCl. Manufacturers have experiencedseveral rate-limiting steps when processing magnesium carbonatehydroxide: batch sizes limited due to the lower density of magnesiumcarbonate hydroxide blends; granulation times of 15 minutes or longer;variability in granulation times of 15 to 37 minutes when usingdifferent lots of magnesium carbonate hydroxide; need for high amountsof water to achieve granulation end points and potentially long dryingtimes based upon initial loss on drying in the range of 23 to 29% (losson drying or “LOD” is a moisture determination test using heat todetermine how much water or solvent is in a product); and limitations inflowability.

Magnesium carbonate hydroxide is also problematic to manufacturersbecause of sourcing concerns.

It can be understood that it would be an improvement to the art if onecould improve the wet granulation processing conditions of an ACEinhibitor-containing formulation without sacrificing the stabilizingeffects of a compound like magnesium carbonate hydroxide.

SUMMARY OF THE INVENTION

It has been discovered that stable compositions containing ACEinhibitors of the type discussed above can be produced using magnesiumoxide as the primary cyclization stabilizer. In one embodiment, apharmaceutical composition is prepared by combining the ACE inhibitor,quinapril HCl, with a stabilizing agent consisting essentially ofmagnesium oxide. Use of magnesium oxide not only minimizes thecyclization degradation of ACE inhibitors, but also improves theformulation of ACE inhibitors into pharmaceutical compositions by thewet granulation technique. In a preferred embodiment, a pharmaceuticalcomposition is prepared by combining the ACE inhibitor with not only astabilizing agent consisting essentially of magnesium oxide, but also anagent that minimizes the hydrolysis of the ACE inhibitor, such as asaccharide, a diuretic, dicalcium phosphate or commonly known fillershaving hydrolysis minimizing effects on the ACE inhibitor. In a morepreferred, a pharmaceutical composition is prepared by combining 5.8 %by weight of magnesium oxide with 5.8 % weight of quinaprilhydrochloride with the inclusion of 88.3 % weight of lactose to yield acomposition which withstands oxidative, hydrolytic, and cyclizationdegradation at 60° C. for 10 days.

In another embodiment, a process is disclosed for preparing stabilizedACE inhibitor-containing compositions with magnesium oxide. The processcomprises the steps of contacting the ACE inhibitor with a suitableamount of a stabilizer consisting essentially of magnesium oxide and oneor more hydrolysis-minimizing agents, such as saccharides, to minimizehydrolysis. In a preferred embodiment, the process comprises the stepsof contacting quinapril HCl with a suitable amount of a stabilizerconsisting essentially of magnesium oxide and one or more saccharides toform a mixture; and subjecting the mixture to wet granulationprocessing.

The compositions of the invention have several advantages overcompositions which do not contain the stabilizing additive. Principally,the active ingredients or drugs contained therein are virtuallyprotected from cyclization and hydrolysis. In addition, thediscoloration which sometimes occurs when ACE inhibitors of this classare formulated and allowed to stand for significant periods of time isminimized or eliminated completely. Thus, a stable tabletted quinaprilformulation can be produced which will undergo no detectable oxidativediscoloration.

In addition to having greater storage stability, the formulations of thepresent inventions are rendered more suitable for use in drugcombinations.

The instant formulations are further advantageous due to the fact thatthe presence of magnesium carbonate hydroxide, and all of its inherentdisadvantages, is unnecessary. Preparation of ACE inhibitor-containingcompositions with magnesium oxide as the principal stabilizer results inimproved processing by a wet granulation technique. Improvements thatdecrease the cost and labor include, but are not limited to an increasein batch sizes due to the high density of magnesium oxide formulations;granulation times of 4.5 to 5 minutes or less; decreased variability ingranulation times (between 0.5 to 1 minute) when using different lots ofmagnesium oxide; decreased amounts of water to achieve granulation endpoints and shorter drying times based upon initial loss on drying (LOD)values in the range of 5% to 8% and improved flowability.

These and other advantages of the invention will become apparent from aconsideration of the following description of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The invention deals with:

I. A pharmaceutical composition which contains:

(a) an effective amount of a drug component which comprises an ACEinhibitor which is susceptible to cyclization, hydrolysis, and/ordiscoloration, and

(b) an effective amount of magnesium oxide and a hydrolysis-minimizingagent suitable to retard cyclization, hydrolysis, and/or discoloration,wherein the magnesium oxide is the principal cyclization stabilizercomponent of the composition.

II. A process for stabilizing an ACE inhibitor drug which comprises thestep of contacting the drug with:

(a) an effective amount of magnesium oxide and a hydrolysis-minimizingagent suitable to retard cyclization, hydrolysis, and/or discoloration,wherein the magnesium oxide is the principal cyclization stabilizercomponent of the composition.

III. A method of making a pharmaceutical dosage form which comprises thestep of including in the formulation suitable amounts of:

(a) an ACE inhibitor, and

(b) magnesium oxide and a hydrolysis-minimizing agent to retardcyclization, hydrolysis, and/or discoloration of the dosage form, themagnesium oxide acting as the principal cyclization stabilizer componentof the dosage form.

Preferably, the compositions and processes made and used in accordancewith the invention will also contain one or more substances which do notinterfere with the function of the stabilizing additive(s). Generally,lubricants, such as magnesium stearate, hydrogenated vegetable oils andtalc, binders, such as gelatin, and/or disintegrants, such aspolyplasdone, are suitable.

Drug Component(s)

The compositions of the invention contain at least one ACE inhibitorand, optionally, one or more other medicament drugs or beneficialsubstances. The ACE inhibitors which can be used in the invention areany of a group of well-known compounds which have antihypertensiveproperties.

One preferred group of compounds includes compounds conforming to thegeneral formula:

wherein A is absent, a fused 5-, 6-, or 7-membered cycloaliphatic ringor a fused benzene ring which is unsubstituted or substituted by 1 or 2alkoxy groups having 1 to 4 carbon atoms; n is 0 or 1, and R is hydrogenor alkyl having 1 to 5 carbon atoms. Preferably A is absent, a fused 5-or 6-membered cycloaliphatic ring or a fused benzene ring which isunsubstituted or substituted by 2 methoxy groups; n is 0 or 1, and R ishydrogen or ethyl.

Particularly valuable are enalapril, quinapril, or indolapril, theircorresponding free acids or pharmaceutically acceptable acid addition orbase salts thereof. Compounds of this type are disclosed in U.S. Pat.Nos. 4,344,949, 4,374,829, and 4,425,355, the disclosure of which arehereby incorporated by reference.

The total drug content of the final composition will be about 1% toabout 70%, preferably from about 1% to about 25%, and most preferablyfrom about 5% to about 8%.

All percentages stated herein are weight percentages based on totalcomposition weight, unless otherwise stated.

The daily dosages of the pharmaceutical preparations of the inventiondepend upon the nature of the dosage form, the nature of the drug(s),and the type and extent of any interactive(s) in drug combinations.Thus, the therapeutic needs of the individual patient and the desires ofthe prescribing physician dictate the dosage levels to be employed. Ingeneral, however, the manufacturer's specifications for any drug or drugcombination are useful guides to administration. The Physicians' DeskReference or other suitable publication can be consulted to ascertainappropriate dosage levels.

Nonetheless, typical dosage levels for quinapril and enalapril are fromabout 1 mg to about 80 mg per dosage.

Suitable categories of drugs that may be employed in addition to ACEinhibitors in the instant compositions may vary widely and generallyrepresent any stable drug combination. Illustrative categories andspecific examples include:

(a) Diuretics, such as hydrochlorothiazide,

(b) Antitussives, such as dextromethorphan, dextromethorphanhydrobromide, noscapine, carbetapentane citrate, and chlophedianolhydrochloride,

(c) Antihistamines, such as chlorpheniramine maleate, phenindaminetartrate, pyrilamine maleate, doxylamine succinate, and phenyltoloxaminecitrate,

(d) Decongestants, such as phenylephedrine hydrochloride,phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, andephedrine,

(e) Various alkaloids, such as codeine phosphate, codeine sulfate, andmorphine,

(f) Mineral supplements such as potassium chloride and the like.

The medicaments and/or other beneficial substances to be used herein maybe selected from a wide variety of substances and pharmaceuticallyacceptable forms thereof, e.g., their acid addition salts. Both organicand inorganic salts may be used provided the drug maintains itsmedicament value. Exemplary acid salts include, but are not limited to,hydrochloride, hydrobromide, orthophosphate, benzoate, maleate,tartrate, succinate, citrate, salicylate, sulfate, acetate, and thelike. Mixtures are operable.

One preferred group of drugs to be used in combination with ACEinhibitors includes: betablockers, diuretics, calcium blockers, and thelike.

Stabilizer(s)

The cyclization and hydrolytic instability which are exhibited bycertain of the drugs discussed above can be overcome via the use of asuitable quantity, i.e., an effective amount of magnesium oxide togetherwith a an agent that minimizes the hydrolysis of the ACE inhibitor, suchas saccharides. While additional stabilizers may be present in thepresent invention, their cyclization stabilizing effects on the ACEinhibitor formulations are minimal in comparison to the stabilizingeffects of the magnesium oxide. Even small amounts of magnesiumcarbonate, which can result from the exposure of magnesium oxide towater and air, will have a minimal stabilizing effect on the ACEinhibitor formulations when compared to the stabilizing effect of themagnesium oxide present in the formulation.

Magnesium oxide, or calcined magnesia, is commercially available fromsuch companies as Dead Sea Periclase of Israel, Lohmann of Germany orMorton International. This compound occurs in nature as the mineralpericlase. Commercial preparation of magnesium ooxide from magnesiteores is described in U.S. Pat. No. 3,320,029.

Magnesium oxide is available in many commercial grades, all of which arewithin the scope of the present invention. Two preferred forms ofmagnesium oxide are a very bulky form termed “Light” and a dense formtermed “Heavy.”

In the preferred embodiment of the invention, the stabilizedACE-inhibitor compositions consist essentially of magnesium oxide as thecyclization stabilizer. The quantity of the magnesium oxide to be usedwill lie between about 1% and 90%, preferably about 1% to about 50%, andmost preferably about 1% to about 10% of the total composition. Ingeneral, any amount which will effectively retard or prevent cyclizationdegradation of the ACE inhibitor component(s) can be used.

Hydrolysis-Minimizing Agent

The hydrolysis-minimizing agents of the present invention act toprotect. the ACE inhibitor from hydrolytic degradation. Thehydrolysis-minimizing agent(s) to be used in the pharmaceutical productsand methods of the invention are substances which are compatible withmagnesium oxide so that they do not interfere with magnesium oxide'sfunction in the composition. Generally, they are substances which do notcontain groups which could significantly interfere with the function ofeither the metal-containing component or the drug component. Preferredhydrolysis-minimizing agents of the present invention are saccharidessuch as mannitol, lactose, and other sugars, diuretics, dicalciumphosphate, hydrochloro thiazide, and known fillers that have ahydrolysis-minimizing effect on the ACE inhibitors. Saccharides are mostpreferred and mixtures are operable.

Generally, the quantity of the hydrolysis-minimizing agent present willbe from about 10% to about 95%, preferably about 50% to about 95%, andmost preferably from about 70% to about 90% of the total composition.

Dosage Forms

The compositions of the present invention can be administered to apatient alone or as part of a composition that contains other componentssuch as excipients, diluents, and carriers, all of which are well-knownin the art. The compositions can be administered to humans and animalseither orally, rectally, parenterally (intravenously, intramuscularly,or subcutaneously), intracistemally, intravaginally, intraperitoneally,intravesically, locally (powders, ointments, or drops), or as a buccalor nasal spray.

The final form of the pharmaceutical preparations made in accordancewith the invention can vary greatly. Orally administrable forms, i.e.tablets, caplets, and capsules, are preferred. Solid, semi-solid, andliquid formulations can be made. However, solids are highly preferred.The optional excipients which can be used in the instant compositionsare also substances which must be compatible with magnesium oxide sothat it does not interfere with its function in the composition.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions, or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents,solvents, or vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), Cremophor EL (a derivativeof castor oil and ethylene oxide; purchased from Sigma Chemical Co., St.Louis, Mo.) and suitable mixtures thereof, vegetable oils (such as oliveoil), and injectable organic esters such as ethyl oleate. Properfluidity can be maintained, for example, by the use of a coating such aslecithin, by the maintenance of the required particle size in the caseof dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride, and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is admixed with at least one inert customary excipient (orcarrier) such as sodium citrate or dicalcium phosphate or (a) fillers orextenders, as for example, starches, lactose, sucrose, glucose,mannitol, and silicic acid; (b) binders, as for example,carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone,sucrose, and acacia; (c) humectants, as for example, glycerol; (d)disintegrating agents, as for example, agar-agar, potato or tapiocastarch, alginic acid, certain complex silicates, modified starch,polyvinylpyrrolidone (cross- or uncross-linked), and modified cellulosederivatives, (e) solution retarders, as for example paraffin; (f)absorption accelerators, as for example, quaternary ammonium compounds;(g) wetting agents, as for example, cetyl alcohol and glycerolmonostearate; (h) adsorbents, as for example, kaolin and bentonite; (i)lubricants, as for example, talc, hydrogenated vegetable oil, zincstearate, calcium stearate, magnesium stearate, solid polyethyleneglycols, sodium lauryl sulfate; 0) pigments; and (k) colorants ormixtures thereof. In the case of capsules, tablets, and pills, thedosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethyleneglycols andthe like.

Solid dosage forms such as tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells, such as entericcoatings and others well-known in the art. They may contain opacifyingagents, and can also be of such composition that they release the activecompound or compounds in a certain part of the intestinal tract in adelayed manner. Examples of embedding compositions which can be used arepolymeric substances and waxes. The active compounds can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art, such as water or othersolvents, solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide, oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, Cremophor EL (a derivative of castor oil andethylene oxide; purchased from Sigma Chemical Co., St. Louis, Mo.),polyethyleneglycols and fatty acid esters of sorbitan or mixtures ofthese substances, and the like.

Besides such inert diluents, the composition can also include adjuvants,such as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents. Suspensions, in addition to the activecompounds, may contain suspending agents, as for example, ethoxylatedisostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agarand tragacanth, or mixtures of these substances, and the like.

Compositions for rectal administrations are preferably suppositorieswhich can be prepared by mixing the compounds of the present inventionwith suitable non-irritating excipients or carriers such as cocoabutter, polyethylene glycol, or a suppository wax, which are solid atordinary temperatures but liquid at body temperature and, therefore,melt in the rectum or vaginal cavity and release the active component.

Dosage forms for topical administration of a compound of this inventioninclude ointments, powders, sprays, and inhalants. The active componentis admixed under sterile conditions with a physiologically acceptablecarrier and any preservatives, buffers, or propellants as may berequired. Ophthalmic formulations, eye ointments, powders, and solutionsare also contemplated as being within the scope of this invention.

The above ACE inhibitor-containing compositions set forth above will beused in therapeutic amounts as indicated in the Physicians' DeskReference (PDR) 47^(th) Edition (1993), which is incorporated herein byreference, or such therapeutically useful amounts as would be known toone of ordinary skill in the art.

The compositions can be administered at the recommended maximum clinicaldosage or at lower doses. Dosage levels of the active compounds in thecompositions of the invention may be varied so as to obtain a desiredtherapeutic response depending on the route of administration, severityof the disease, and the response of the patient. The determination ofoptimum dosages for a particular patient is well known to those skilledin the art.

Processing

The present invention is directed to a process for stabilizing an ACEinhibitor drug which comprises the step of contacting an effectiveamount of the drug with an effective amount of magnesium oxide and ahydrolysis-minimizing agent suitable to retard cyclization, hydrolysis,and/or discoloration, wherein the magnesium oxide is the principalcyclization stabilizer component of the composition. While anytechniques known to those of skill in the art for contacting the drugand the magnesium oxide, and which are appropriate, can be employed, awet granulation process is preferred. The presence of magnesium oxidelends itself to improved wet granulation processing of ACEinhibitor-containing compositions, the advantages of which are discussedbelow in detail in Example 6 where a comparison is made of previouslyknown magnesium carbonate hydroxide formulations and the magnesium oxideformulations of the present invention. A summary of these advantages isas follows:

(1) magnesium oxide formulations are dense and can allow an increase inbatch sizes using current equipment;

(2) a decrease in granulation times, the granulation times ranging fromabout 4.5 to about 5 minutes or less;

(3) a decrease in the variability in granulation times, the variabilityranging from about 0.5 to about 1 minute when using different lots ofmagnesium oxide;

(4) a decrease in the amounts of water required to achieve granulationend points and potentially shorter drying times, the amounts of waterrequired is from about 50% or less and drying times of about 7 minutes;

(5) initial LODs in the range of 5 to 8%;

(6) an improvement in the flowability or angle of repose test wheremagnesium oxide formulations had a flowability or angle of repose of32°.

In a preferred embodiment, the present invention is directed to aprocess for preparing a stabilized pharmaceutical composition comprisingan effective amount of an ACE inhibitor and a hydrolysis-minimizingagent and consisting essentially of an effective amount of magnesiumoxide as the cyclization stabilizing agent, wherein the processcomprises:

(1) blending together a suitable amount of an ACE inhibitor, ahydrolysis-minimizing agent and magnesium oxide;

(2) adding a granulating fluid to the blend to form a moist mass;

(3) drying the granules; and

(4) blending the granules with pharmaceutically inactive excipients.

The process further comprises the optional steps of screening the driedgranules before addition of the pharmaceutically inactive excipients.The granulation medicament so formed may then be subjected to furtherconventional processing to form various solid dosage forms. The soliddosage forms may then be processed into final dosage forms byconventional techniques.

The percentages in which excipients are used are not critical. Ingeneral, their quantities will be consistent with the amount given abovefor the drug and stabilizer components (disintegrant about 1% to about15% of the total composition; lubricant about 0.1% to about 5% of thetotal composition; and binder about 1% to about 10% of the totalcomposition), i.e., they make up the remainder of the composition.

The drug preparations can be adapted for immediate, slow, or sustainedrelease profiles, or any combination of these. Thus, a formulationadapted to give an initial loading dosage within 30 minutes followed bysustained release of the remaining drug over 4 to 12 hours iscontemplated. Sustained and immediate release formulations arepreferred. Reasonable variations, such as those which would occur to askilled artisan, can be made herein without departing from the scope ofthe invention.

The examples presented below are intended to illustrate particularembodiments of the invention, and are not intended to limit the scope ofthe specification or the claims in any way.

EXAMPLE 1

The following materials were processed by wet granulation method for themanufacture of 20-mg tablets.

Quinapril Hydrochloride 21.7 mg Magnesium Oxide 21.7 mg Lactose 254.3 mgGelatin 6.4 mg Polyplasdone 12.8 mg Magnesium Stearate 3.2 mg

EXAMPLE 2

The following materials were processed by wet granulation for themanufacture of 5-mg tablets without the addition of a stabilizer.

Quinapril Hydrochloride 5.425 g Lactose Anhydrous 119.575 gMicrocrystalline Cellulose 14.775 g Disodium EDTA 0.225 g Sterotex HM1.500 g Syloid 244 Silica Gel 3.000 g Stearic Acid 4.500 g Ascorbic AcidUSP 1.000 g Water, Purified USP 2.250 g

EXAMPLE 3

The following materials were processed by wet granulation for themanufacture of 20-mg tablets without the addition of a stabilizer of thepresent invention.

Quinapril Hydrochloride 21.7 mg Magnesium Carbonate Hydroxide 125.0 mgLactose 33.3 mg Gelatin 10.0 mg Polyplasdone 8.0 mg Magnesium Stearate2.0 mg

EXAMPLE 4

Stability of the tablets prepared in Examples 1 and 3 were tested at 60°C. for 10 days. The data shows that the use of magnesium oxideeffectively stabilizes ACE inhibitor-containing compositions such asquinapril HCl compositions when compared against similar formulationsthat do not contain a stabilizer (Example 2) or contain magnesiumcarbonate hydroxide (Example 3). The data not only shows that magnesiumoxide stabilizes ACE inhibitor-containing compositions as well asmagnesium carbonate hydroxide, but also that the magnesium oxideformulation requires less gelatin (about 2%) than the magnesiumcarbonate hydroxide formulation (about 5%) to obtain acceptablecompressability.

Degradation Products (%) Quinapril (%) Hydrolysis Initial/10 DaysDiketopiperazine Product Example 1 98.7/98.9 — — Example 2^(a,b) 68.132.4 <1 Example 3 97.7/96.1 — — ^(a)Percent of original quinaprilcontent ^(b)Analysis was carried out after 1 month at 60° C.

EXAMPLE 5

Quinapril formulations containing magnesium oxide and quinaprilformulations containing magnesium carbonate hydroxide were prepared forcomparison in wet granulation processing. The formulations (1.5 kgs MgOand 1.5 kgs MgCO₃)were prepared by combining the following ingredients:

Quinapril HCl 162.5 g  101.7 g  Magnesium Oxide — 101.7 g  MagnesiumCarbonate 937.5 g  — Hydroxide Lactose 250.0 g  1191.6 g  Gelatin 75.0 g30.0 g Polyplasdone 60.0 g 60.0 g Magnesium Stearate 15.0 g 15.0 g

Results

The magnesium oxide formulations were denser than the magnesiumcarbonate hydroxide formulations. 2.5 kgs of the magnesium oxideformulations were able to be granulated in a 10 L Gral when compared to1.5 kgs of magnesium carbonate hydroxide formulations. The bulk densityof the blends prior to the addition of the gelatin solution was 0.70g/mL for quinapril/magnesium oxide and 0.27 g/mL for quinapril/magnesiumcarbonate hydroxide.

The granulation time was shorter (4.5 to 5 minutes) with the magnesiumoxide formulations compared to magnesium carbonate hydroxideformulations (15 to 37 minutes).

The variability in granulation times was decreased; about 15 to 17minutes using different lots of magnesium carbonate hydroxide and 0.5 to1 minute using different lots of magnesium oxide.

The quantity of water used to achieve granulation end point wasdecreased; magnesium oxide used 50% less water than magnesium carbonatehydroxide formulations.

The initial LOD for the magnesium oxide formulations was in the range of5% to 8% compared to 23% to 29% for the magnesium carbonate hydroxideformulations.

The magnesium oxide formulations dried faster (7 minutes) than themagnesium carbonate hydroxide formulations (15-18 minutes).

A second wet milling step was avoided in the magnesium oxideformulations because no lumps with moisture in them were observed unlikethe magnesium carbonate hydroxide formulations.

The flowability or angle of repose test indicated that the magnesiumoxide formulations had better flowability (32° angle of repose) than themagnesium carbonate formulations (35° angle of repose).

Only one formulation containing magnesium oxide was necessary to deliveror manufacture quinapril HCI in four strengths (5, 10, 20 and 40 mg)compared to the two formulations required to deliver quinapril HCl in5/10 mg and 20/40 mg strengths.

What is claimed is:
 1. A process for stabilizing a drug quinaprilagainst cyclization which comprises the step of contacting the drugwith: (a) a suitable amount of magnesium oxide to retard cyclization,wherein the magnesium oxide is a principal stabilizer, and (b) one ormore saccharide,s wherein the saccharides is a hydrolysis-minimizingagent.
 2. The process of claim 1 wherein the process further comprisesthe steps of: blending together a suitable amount of quinipril, one ormore saccharides and magnesium oxide; adding a granulating fluid to theblend to form a moist mass; drying granules; and blending the granuleswith pharmaceutically inactive excipients.
 3. The process of claim 2wherein the process further comprises the steps of: screening the driedgranules once before addition of the pharmaceutically inactiveexcipients.